Schüle R, Rangarajan P, Yang N, Kliewer S, Ransone L J, Bolado J, Verma I M, Evans R M
Howard Hughes Medical Institute, La Jolla, CA.
Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6092-6. doi: 10.1073/pnas.88.14.6092.
We present evidence that retinoic acid can down-regulate transcriptional activation by the nuclear protooncogene c-jun. All three members of the retinoic acid receptor (RAR) subfamily (RAR alpha, RAR beta, and RAR gamma) can repress transcriptional induction of the human collagenase gene or a heterologous promoter that contains the collagenase promoter AP-1-binding site. In contrast, the retinoid X receptor fails to repress Jun/AP-1 activity, demonstrating a significant difference between the two regulatory systems through which retinoids exert their transcriptional control. Analysis of RAR alpha mutants in transfection studies reveals that the DNA-binding domain is important for the inhibition of Jun/AP-1 activity, even though the RAR does not bind the collagenase AP-1 site. Rather, gel-retardation assays reveal that bacterially expressed full-length RAR alpha inhibits binding of Jun protein to target DNA. These data suggest that the RAR alpha may form a nonproductive complex with c-Jun and provides a simple mechanisms by which retinoic acid may limit cell growth and possibly malignant progression.
我们提供的证据表明，视黄酸可以下调核原癌基因c-jun的转录激活作用。视黄酸受体（RAR）亚家族的所有三个成员（RARα、RARβ和RARγ）都能抑制人胶原酶基因或含有胶原酶启动子AP-1结合位点的异源启动子的转录诱导。相比之下，类视黄醇X受体不能抑制Jun/AP-1活性，这表明类视黄醇发挥转录调控作用的两种调节系统之间存在显著差异。转染研究中对RARα突变体的分析表明，尽管RAR不与胶原酶AP-1位点结合，但DNA结合结构域对于抑制Jun/AP-1活性很重要。相反，凝胶阻滞试验表明，细菌表达的全长RARα抑制Jun蛋白与靶DNA的结合。这些数据表明，RARα可能与c-Jun形成无活性复合物，并提供了一种简单的机制，通过该机制视黄酸可能限制细胞生长并可能抑制恶性进展。
